International Immunology, Vol 9, 1375-1384, Copyright © 1997 by Oxford University Press
DT Chao and SJ Korsmeyer
Thymocyte differentiation progresses through well-defined stages in which
apoptosis is central to the selection of a functional TCR repertoire. In
the present study, we explored the developmental effects of BCL-XL, a
repressor of apoptosis. We found that endogenous BCL-XL is down-regulated
by both positive and negative selection signals at the CD4+ CD8+ stage of
thymocyte development. We examined the role of BCL- XL regulatable
apoptosis in T cell development in the context of an alpha beta TCR
transgene, Rag-1 deficiency and the scid model. We found that BCL-XL
expression promoted accumulation of CD8 single-positive thymocytes even in
MHC class II-restricted TCR transgenic mice. However, the apoptotic
resistance conferred by BCL-XL could not fully substitute for TCR-mediated
positive selection signals nor did it prevent negative selection.
Overexpression of BCL-XL promoted partial maturation of CD4-CD8- thymocytes
to CD4+CD8+ cells in a Rag-deficient, but not a scid background. Thus,
TCR-mediated signals mediate the regulation of endogenous BCL-XL during
thymocyte development, indicating that the principal protection of
double-positive thymocytes by BCL-XL occurs prior to selection. The impact
of BCL-XL on the CD8 but not CD4 lineage supports the asymmetric model of
lineage commitment. Moreover, several critical control points in T cell
development could be distinguished as BCL-XL responsive or unresponsive.
ARTICLES
BCL-XL-regulated apoptosis in T cell development
Howard Hughes Medical Institute, Department of Medicine and Pathology, Washington University School of Medicine, St Louis, MO 63110, USA.
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